Pharmacokinetic parameters of artesunate and dihydroartemisinin in rats infected with Fasciola hepatica

OBJECTIVES: The pharmacokinetic (PK) parameters of artesunate, recently discovered to possess promising trematocidal activity, and its main metabolite dihydroartemisinin (DHA) were determined in rats infected with hepatic and biliary stages of Fasciola hepatica and compared with uninfected rats after single intragastric and intravenous (iv) doses. METHODS: Rats infected with F. hepatica for 25 and 83 days and uninfected rats were cannulated in the right jugular vein and blood samples were withdrawn at selected timepoints following 10 mg/kg of iv and a single 100 mg/kg oral dose of artesunate. Plasma was analysed for artesunate and DHA by liquid chromatography coupled to tandem mass spectrometry. RESULTS: Rats harbouring juvenile and adult F. hepatica infections revealed considerable changes in PK parameters of artesunate and DHA. Following oral administration, maximum plasma concentrations (C(max)) of artesunate and DHA were 1.8-2.3-fold higher in infected rats [artesunate: 1334 +/- 1404 ng/mL (no infection) versus 2454 +/- 1494 ng/mL (acute infection) and 2768 +/- 538 ng/mL (chronic infection); DHA: 3802 +/- 2149 ng/mL (no infection) versus 6507 +/- 3283 ng/mL (acute infection) and 9093 +/- 884 ng/mL (chronic infection)]. The AUCs of artesunate and DHA were 2.1-4.4-fold greater in infected rats. An opposite trend was observed after iv injection. C(max) and AUC of artesunate and DHA following iv dosing were 5784 +/- 3718 and 140 938 +/- 128 783 ng.min/mL and 3849 +/- 3060 and 86 107 +/- 41 863 ng.min/mL, respectively, in uninfected rats versus 2623 +/- 1554 and 21 617 +/- 12 230 ng.min/mL and 2835 +/- 980 and 64 290 +/- 29 057 ng.min/mL, respectively, in rats harbouring a chronic infection. The elimination half-lives (t(1/2)) of artesunate and DHA were considerably altered in infected rats following oral and iv administration of artesunate. CONCLUSIONS: F. hepatica infections strongly influence the disposition kinetics of artesunate and its metabolite in rats. The clinical implications of this finding need to be carefully studied.

Anorectal anomalies associated with or as part of other anomalies.

Anorectal anomalies occurring with other anomalies or as part of syndromes were analyzed to determine how their epidemiological characteristics differed from those of isolated anal anomalies. Almost 15% of cases were chromosomal, monogenic or teratogenic syndromes, whereas the rest were of unknown cause including sequences (9.3%), VACTERL associations (15.4%) and multiple congenital anomalies (MCA) (60.2%). Almost half of babies with MCA had one or two VACTERL anomalies with distribution frequencies that did not differ significantly from those in babies with the full VACTERL association. There were considerable differences in the frequency of the VACTERL association among babies with different types of anorectal anomaly. Babies with anal anomalies occurring with sequences, VACTERL or MCA showed the same sex differences as babies with isolated anal anomalies, namely male predominance in anal atresia without fistula or cloaca, no sex difference in anal atresia with fistula, and female predominance in ectopic anus and congenital anal fistula. These anomalies, however, were associated with significantly lower mean gestational lengths and birth weights, and higher frequencies of fetal death and pregnancy termination than babies with isolated anal anomalies. Twins were more frequent in sequences, VACTERL and MCA than in isolated anomalies, monogenic syndromes or chromosome anomalies. Five cases were conjoined twins, representing 15% of all cases of twin pregnancies with an anal anomaly. Indeterminate sex was more frequent in babies with anal atresias without fistula than in those with fistula. Anal anomalies are defects of blastogenesis attributable to disorders in expression of pattern determining genes. The differential sex involvement in different types of anal anomaly may be manifestations of expression of the HY/SRY genes during blastogenesis or of X-linkage.

What is the Omega-Loop Gastric Bypass and Why is it Criticized?

The omega-loop gastric bypass (OLGBP), also called "mini-gastric bypass" or "single-anastomosis" gastric bypass is a form of gastric bypass where a long, narrow gastric pouch is created and anastomosed to the jejunum about 200- 250 cm from the angle of Treitz in an omega loop fashion, thereby avoiding a jejuno-jejunostomy.Proponents of the OLGBP claim that it is a safer and simpler operation than the traditional Roux-en-Y gastric bypass (RYGBP), easier to teach, that gives the same results in terms of weight loss than the RYGBP. One randomized study comparing the two techniques showed similar results after five years.The OLGBP is criticized because it creates an anastomosis between the gastric pouch and the jejunum where a large amount of biliopancreatic juices travel, thereby creating a situation where reflux of the latter into the stomach and distal esophagus is likely to develop. Such a situation has clearly been associated, in several animal studies, with an increased incidence of gastric cancer, especially at or close to the gastro-jejunostomy, and with an increased risk of lower esophageal cancer. In clinical practice, omega-loop gastrojejunostomies such as those used for reconstruction after gastric resection for benign disease or distal gastric cancer have been associated with the so called classical anastomotic cancer, linked to biliary reflux into the stomach, despite the fact that epidemiological studies about this do not show uniform results. Although no evidence at the present time links OLGBP to an increased risk of gastric cancer in the human, this possibility raises a concern among many bariatric surgeons, especially in the view that bariatric surgery is performed in relatively young patients with a long life expectancy, hence prone to develop cancer if indeed the risk is increased. Another arguments used against the OLGBP is that the jejuno-jejunostomy in the traditional RYGBP is easy to perform and associated with virtually no complication.Supporters of the OLGBP claim that the liquid that refluxes into the stomach after their procedure is not pure bile and pancreatic juice, but a combination of those with jejunal secretions, and that the latter is not as harmful. We would urge the proponents of the OLGBP to undertake the necessary animal studies to show that their assumption is indeed true before the procedure is performed widely, possibly leading to the development of hundreds of late gastric or esophageal carcinoma in the bariatric population. In the meantime, we strongly believe that RYGBP should remain the gold standard in gastric bypass surgery for morbid obesity.

Evaluation of peripheral arterial bypass grafts with multi-detector row CT angiography: comparison with duplex US and digital subtraction angiography.

PURPOSE: To assess the technical feasibility of multi-detector row computed tomographic (CT) angiography in the assessment of peripheral arterial bypass grafts and to evaluate its accuracy and reliability in the detection of graft-related complications, including graft stenosis, aneurysmal changes, and arteriovenous fistulas. MATERIALS AND METHODS: Four-channel multi-detector row CT angiography was performed in 65 consecutive patients with 85 peripheral arterial bypass grafts. Each bypass graft was divided into three segments (proximal anastomosis, course of the graft body, and distal anastomosis), resulting in 255 segments. Two readers evaluated all CT angiograms with regard to image quality and the presence of bypass graft-related abnormalities, including graft stenosis, aneurysmal changes, and arteriovenous fistulas. The results were compared with McNemar test with Bonferroni correction. CT attenuation values were recorded at five different locations from the inflow artery to the outflow artery of the bypass graft. These findings were compared with the findings at duplex ultrasonography (US) in 65 patients and the findings at conventional digital subtraction angiography (DSA) in 27. RESULTS: Image quality was rated as good or excellent in 250 (98%) and in 252 (99%) of 255 bypass segments, respectively. There was excellent agreement both between readers and between CT angiography and duplex US in the detection of graft stenosis, aneurysmal changes, and arteriovenous fistulas (kappa = 0.86-0.99). CT angiography and duplex US were compared with conventional DSA, and there was no statistically significant difference (P >.25) in sensitivity or specificity between CT angiography and duplex US for both readers for detection of hemodynamically significant bypass stenosis or occlusion, aneurysmal changes, or arteriovenous fistulas. Mean CT attenuation values ranged from 232 HU in the inflow artery to 281 HU in the outflow artery of the bypass graft. CONCLUSION: Multi-detector row CT angiography may be an accurate and reliable technique after duplex US in the assessment of peripheral arterial bypass grafts and detection of graft-related complications, including stenosis, aneurysmal changes, and arteriovenous fistulas.

Impact of induction therapy on airway complications after sleeve lobectomy for lung cancer.

BACKGROUND: Sleeve lobectomy is a valid alternative to pneumonectomy for the treatment of centrally located operable non-small cell lung cancer (NSCLC), but concern has been evoked regarding a potentially increased risk of bronchial anastomosis complications after induction therapy. This study examined the impact of induction therapy on airway healing after sleeve lobectomy for NSCLC. METHODS: Bronchial anastomosis complications were recorded with respect to the induction regimen applied (neoadjuvant chemotherapy vs chemoradiotherapy) in a consecutive series of patients with sleeve lobectomy for NSCLC. RESULTS: Ninety-nine patients underwent sleeve resection, 28 of them after induction therapy. Twelve patients received chemotherapy alone, and 16 patients had radiochemotherapy. There were no significant differences in postoperative 90-day mortality (3.6% vs 2.8%) and morbidity (54% vs 49%) for patients with and without induction therapy. Bronchial anastomosis complications occurred in 3 patients (10.8%) with neoadjuvant therapy and in 2 (2.8%) without (p = 0.3). In the induction therapy group, two bronchial stenoses occurred after radiochemotherapy and one bronchopleural fistula after chemotherapy alone. In patients without induction therapy, one bronchial stenosis and one bronchopleural fistula were observed. All bronchial stenoses were successfully treated by dilatation, and both bronchopleural fistulas occurring after right lower lobectomy were successfully treated by reoperation and completion sleeve bilobectomy with preservation of the upper lobe. CONCLUSIONS: Sleeve lobectomy for NSCLC can be safely performed after induction chemotherapy and radiochemotherapy with mortality and incidence of airway complications similar to that observed in nonpretreated patients. The treatment of airway complications does not differ for patients with and without induction therapy.

Total and segmental liver volume variations: implications for liver surgery.

BACKGROUND: Liver remnant volumes after major hepatic resection and graft volumes for liver transplantation correlate with surgical outcome. The relative contributions of the hepatic segments to total liver volume (TLV) are not well established. METHODS: TLV and hepatic segment volumes were measured with computed tomography (CT) in 102 patients without liver disease who underwent CT for conditions unrelated to the liver or biliary tree. RESULTS: TLV ranged from 911 to 2729 cm(3). On average, the right liver (segments V, VI, VII, and VIII) contributed approximately two thirds of TLV (997+/-279 cm(3)), and the left liver (segments II, III and IV) contributed approximately one third of TLV (493+/-127 cm(3)). Bisegment II+III (left lateral section) contributed about half the volume of the left liver (242+/-79 cm(3)), or 16% of TLV. Liver volumes varied significantly between patients--the right liver varied from 49% to 82% of TLV, the left liver, 17% to 49% of TLV, and bisegment II+III (left lateral section) 5% to 27% of TLV. Bisegment II+III contributed less than 20% of TLV in more than 75% of patients and the left liver contributed 25% or less of TLV in more than 10% of patients. DISCUSSION: There is clinically significant interpatient variation in hepatic volumes. Therefore, in the absence of appreciable hypertrophy, we recommend routine measurement of the future liver remnant before extended right hepatectomy (right trisectionectomy) and in selected patients before right hepatectomy if a small left liver is anticipated.

A new poly(ortho ester)-based drug delivery system as an adjunct treatment in filtering surgery.

PURPOSE: Pharmacologic modulation of wound healing after glaucoma filtering surgery remains a major clinical challenge in ophthalmology. Poly(ortho ester) (POE) is a bioerodible and biocompatible viscous polymer potentially useful as a sustained drug delivery system that allows the frequency of intraocular injections to be reduced. The purpose of this study was to determine the efficacy of POE containing a precise amount of 5-fluorouracil (5-FU) in an experimental model of filtering surgery in the rabbit. METHODS: Trabeculectomy was performed in pigmented rabbit eyes. An ointmentlike formulation of POE containing 1% wt/wt 5-FU was injected subconjunctivally at the site of surgery, during the procedure. Intraocular pressure (IOP), bleb persistence, and ocular inflammatory reaction were monitored until postoperative day 30. Quantitative analysis of 5-FU was performed in the anterior chamber. Histologic analysis was used to assess the appearance of the filtering fistula and the polymer's biocompatibility. RESULTS: The decrease in IOP from baseline and the persistence of the filtering bleb were significantly more marked in the 5-FU-treated eyes during postoperative days 9 through 28. Corneal toxicity triggered by 5-FU was significantly lower in the group that received 5-FU in POE compared with a 5-FU tamponade. Histopathologic evaluation showed that POE was well tolerated, and no fibrosis occurred in eyes treated with POE containing 5-FU. CONCLUSIONS: In this rabbit model of trabeculectomy, the formulation based on POE and containing a precise amount of 5-FU reduced IOP and prolonged bleb persistence in a way similar to the conventional method of a 5-FU tamponade, while significantly reducing 5-FU toxicity.

Transient suppression of Shigella flexneri type 3 secretion by a protective O-antigen-specific monoclonal IgA.

Mucosal immunity to the enteric pathogen Shigella flexneri is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of S. flexneri serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for S. flexneri to gain entry into intestinal epithelial cells. IgAC5's effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5's effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of S. flexneri partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells. IMPORTANCE: Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by "immune exclusion," a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.

Transcatheter coil embolization of multiple bilateral congenital coronary artery fistulae.

Coronary artery fistulae represent the most frequent congenital anomalies of the coronary arteries, but remain a relatively uncommon clinical problem. Moreover, multiple fistulae originating from both the left and the right coronary arteries and draining into the left ventricular chamber are a rare condition. Due to the low prevalence of these anomalies, the appropriate management of patients with symptomatic coronary artery fistulae is controversial. Transcatheter closure approaches have emerged as a less invasive strategy and are nowadays considered a valuable alternative to surgical correction with similar effectiveness, morbidity and mortality. The percutaneous management, however, is mainly limited by the individual anatomic features of the fistula and an appropriate patient's selection is considered as a key determining factor to achieve complete occlusion. Thus, success rates of transcatheter closure techniques reported in the literature are extremely variable and highly dependent upon the nature of the follow up, which, at present, is not standardized. The optimal management of symptomatic patients with multiple coronary artery fistulae still remains a challenging problem and has been traditionally considered as an indication for cardiac surgery. We report here the case of a patient with double bilateral congenital coronary artery fistulae arising from both the left and right coronary arteries and draining individually into the left ventricular chamber. This patient underwent successful transcatheter anterograde closure of both fistulae using a microcoil embolization technique.

Myéloradiculopathie chronique progressive chez un homme de 61 ans [Chronic progressive myeloradiculopathy in a 61-year-old man]

A painful worsening of known difficulties in walking led us to investigate a man who presented a spastic paraparesis. Radiological investigations had to be repeated three times before making a diagnosis of a right C6 spinal dural arteriovenous fistula after a 22-month follow-up. Knowing the mechanisms leading to spinal venous hypertension may explain the low yield of the early radiological investigations that should be repeated. The efficiency of the treatment depends on the severity of the presurgical neurologic manifestations.

Predictors for hospitalization and outpatient visits in patients with inflammatory bowel disease: results from the Swiss Inflammatory Bowel Disease Cohort Study.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) have a high resource consumption, with considerable costs for the healthcare system. In a system with sparse resources, treatment is influenced not only by clinical judgement but also by resource consumption. We aimed to determine the resource consumption of IBD patients and to identify its significant predictors. MATERIALS AND METHODS: Data from the prospective Swiss Inflammatory Bowel Disease Cohort Study were analysed for the resource consumption endpoints hospitalization and outpatient consultations at enrolment [1187 patients; 41.1% ulcerative colitis (UC), 58.9% Crohn's disease (CD)] and at 1-year follow-up (794 patients). Predictors of interest were chosen through an expert panel and a review of the relevant literature. Logistic regressions were used for binary endpoints, and negative binomial regressions and zero-inflated Poisson regressions were used for count data. RESULTS: For CD, fistula, use of biologics and disease activity were significant predictors for hospitalization days (all P-values <0.001); age, sex, steroid therapy and biologics were significant predictors for the number of outpatient visits (P=0.0368, 0.023, 0.0002, 0.0003, respectively). For UC, biologics, C-reactive protein, smoke quitters, age and sex were significantly predictive for hospitalization days (P=0.0167, 0.0003, 0.0003, 0.0076 and 0.0175 respectively); disease activity and immunosuppressive therapy predicted the number of outpatient visits (P=0.0009 and 0.0017, respectively). The results of multivariate regressions are shown in detail. CONCLUSION: Several highly significant clinical predictors for resource consumption in IBD were identified that might be considered in medical decision-making. In terms of resource consumption and its predictors, CD and UC show a different behaviour.

La lymphadénite à mycobactérie atypique [Lymphadenitis due to atypical mycobacteria]

La lymphadénite est une maladie courante dans l'enfance et un motif fréquent de consultation pédiatrique ou ORL. Elle est habituellement due à une infection des voies respiratoires hautes et est autolimitée. Chez l'enfant présentant une lymphadénite cervicale subaiguë ou chronique qui ne répond pas aux antibiotiques habituels, une infection à mycobactérie atypique doit être évoquée. L'infection touche surtout les enfants en bonne santé entre un et cinq ans. Le diagnostic précoce est essentiel car le traitement de choix est l'exérèse des ganglions atteints, avant l'apparition d'une nécrose cutanée et d'une fistulisation. Cet article revoit les présentations cliniques spécifiques, les méthodes diagnostiques et le traitement des lymphadénites à mycobactéries atypiques. Cervical lymphadenitis is common in childhood and is a frequent source of consultation at the pediatrician's or ENT's office. It is usually caused by a viral upper respiratory tract infection and is self limited. In children with subacute or chronic cervical lymphadenitis which fails to respond to conventional antibiotics, infection due to atypical mycobacteria should always be considered. Infections occur predominantly in an otherwise healthy child of 1 to 5 years of age. The early diagnosis is essential as the treatment of choice is early surgical excision before skin necrosis and fistula occur. This article reviews the specific clinical manifestations, diagnostic tools and treatment of lymphadenitis due to atypical mycobacteria.

Removal of unusual, large high-velocity metallic maxillary sinus foreign bodies by a modified free bone flap technique.

Metallic foreign bodies are rarely found in the maxillary sinus, and usually they have a dental origin.Potential complications related to foreign bodies include recurrent sinusitis, rhinolith formation, cutaneous fistula,chemical poisoning, facial neuralgic pain and even malignancies.Two main surgical approaches are currently used for the removal of foreign bodies in the maxillary sinus: the bone flap and the endoscopic sinus techniques. We are reporting two unusual cases of large high-velocity foreign bodies removed by a modified maxillary lateral antrotomy,with free bone flap repositioning and fixation with a titanium miniplate.

Fistulizing Crohn's disease.

Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%). Medical therapy is the main option for perianal fistula once abscesses, if present, have been drained, and should include antibiotics (both ciprofloxacin and metronidazole) and immunomodulators. Infliximab should be reserved for refractory patients. Surgery is often necessary for internal fistulas.

The potential of metastatic lymph nodes to predict positive resection margins in patients with resectable pancreatic cancer

Objective: Despite progress during recent decades, long-term outcome¦of patients with pancreatic cancer remains dismal. Since positive resection¦margins and metastatic lymph nodes are known risk factors for early tumor¦recurrence, patients at risk should be identified and could potentially benefit¦from preoperative radio-chemotherapy. This study aimed to assess whether the¦presence of lymph node metastasis could be used to predict positive resection¦margins in patients with pancreatic cancer.¦Methods: A series of 146 patients (82 male, 64 female, median age 68 years)¦underwent pancreatic head resection for various malignant diseases (pancreatic¦ductal adenocarcinoma, biliary cancer, periampullary cancer) at our institution¦from 2000 to 2011. Patients were identified from our prospective database¦that collects more than 60 single items of all patients undergoing pancreatic¦resection. Lymph node metastasis and positive resection margins were all¦confirmed by histological evaluation. Positive predictive value (PPV), negative¦predictive value (NPV), sensitivity and specificity were calculated to assess¦the predictive value of metastatic lymph nodes regarding tumor-free (R0) and¦tumor-involved (R1) resection margins.¦Results: There were 110 specimens (76%) with tumor-positive lymph nodes¦and 36 specimens with tumor-negative lymph nodes. Resection margins were¦positive in 47 specimens (32%) and negative in 99 specimens. Sensitivity of¦tumor-positive lymph nodes to detect positive resection margins was 96%, and¦the NPV was 94%. In contrast, specificity was 34% and the PPV was 41%.¦Conclusion: Patients with resectable pancreatic cancer, who have no lymph¦node metastasis, are at very low risk to have positive resection margins (2 of¦36 patients, NPV 94%). In contrast, more than one third of patients with¦metastatic lymph nodes are at increased risk for an incomplete tumor resection¦(sensitivity 96%). If lymph nodesmetastases are highly suspected at preoperative¦staging, a neoadjuvant treatment strategy should be considered to increase the¦R0 resection rate.